Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding)

Martinez Lopez JA, Loza E, Carmona L

CRD summary

The authors concluded that there was insufficient data on the safety and risks of methotrexate used for treating rheumatoid arthritis during conception, pregnancy and lactation. There were some limitations to the review, but overall the authors’ conclusion reflected the limited evidence and is likely to be reliable.

Authors' objectives

To evaluate the safety of methotrexate used for treating rheumatoid arthritis with respect to reproductive outcomes (fertility, pregnancy and breast-feeding).

Searching

MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1961 to October 2007. Some details of the search strategy were reported. In addition, reference lists and annual scientific meetings of the American College of Rheumatology and the European League Against Rheumatism (2005 to 2007) were screened. No language restrictions were applied.

Study selection

Randomised controlled trials (RCTs), cohort studies, longitudinal observational studies and surveys that evaluated the effects of methotrexate at doses used in rheumatology (7.5 to 25mg per week), in adults (aged over 18 years) with rheumatoid arthritis, were eligible for inclusion. Studies had to evaluate the following: male or female fertility; pregnancy complications, malformations, miscarriages, induced abortions and still births; breast feeding complications, infections, immunosuppression; or dose of methotrexate in human milk.

In the included studies of methotrexate and pregnancy, the mean methotrexate dose ranged from 5 to 25mg per week, women were exposed to methotrexate from conception to the first trimester of pregnancy, and their mean age ranged from 28 to 35 years (where reported).

Two reviewers independently selected studies and resolved disagreements by consensus.

Assessment of study quality

The authors did not state that they assessed validity. They did grade the level of evidence provided by each study using the hierarchy of study design described by the Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001 adaptation), in which level 4 represents case-series or poor quality cohort and case-control series, and level 5 represents expert opinion.

Data extraction

For each study, the number of events of interest and percentages were recorded.

The studies were combined in a narrative synthesis. Overall rates of events of interest were calculated.

Results of the review

Six studies were included in the review (n=101 methotrexate exposed pregnancies). None of the studies were classified as providing higher than level 4 evidence. All of the studies were descriptions of cases detected by retrospectively searching patient records or surveys of patients and of doctors.

Methotrexate and pregnancy: Overall rates of events of interest were as follows: 19 miscarriages (representing 19% of all pregnancies and 23% of pregnancies in which abortion was not induced); 55 live births (representing 54% of all pregnancies and 66% of pregnancies in which abortion was not induced); and five neonatal malformations (representing 4% of all pregnancies and 5% of pregnancies in which abortion was not induced). None of the neonatal malformations were described as aminopterin syndrome (a syndrome which has been described in methotrexate exposed pregnancies). The rate of induced abortions was 18%.

No studies met the inclusion criteria for the evaluation of the effects of methotrexate on lactation or male fertility.

Authors' conclusions

There was a lack of data on the safety and risks of methotrexate at doses used in rheumatology during conception, pregnancy and lactation. There was insufficient evidence to determine if it was methotrexate or rheumatoid arthritis that was associated with miscarriage. Rates of miscarriage and birth defects were similar to rates observed in healthy populations.

CRD commentary

The review question was clearly stated and inclusion criteria were appropriately defined. The broad inclusion criteria for study design were justified in view of the paucity of identified studies. Several relevant sources were searched. No language restrictions were applied, but no attempts were made to minimise publication bias. Methods were used to minimise reviewer errors and bias in the selection of studies and extraction of data.

Study validity was not assessed, but the level of evidence was reported giving some indication of the limited quality of the included studies. Appropriate methods were used to combine the studies.

There were some limitations to the review, but overall the authors’ conclusion reflected the limited evidence and is likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that rheumatologists should discourage patients who wish to become pregnant from continuing with methotrexate. It is not clear whether the best option for patients who become pregnant while on methotrexate is an induced abortion or continuing with the pregnancy; any continuing pregnancy should be carefully monitored.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.